F. M. Singer et al., "New Inhibitors of in vitro Conversion of Acetate and Mevalonate to Cholesterol", Proc. Soc. Exper. Biol. Med., 102, 370 (1959) and F. H. Hulcher, "Inhibition of Hepatic Cholesterol Biosynthesis by 3,5-Dihydroxy-3,4,4,-trimethylvaleric Acid and its Site of Action," Arch. Biochem. Biophys., 146, 422 (1971) disclose that certain mevalonate derivatives inhibit the biosynthesis of cholesterol.
Singer et al. reported that fluoromevalonic acid is more effective in inhibiting biosynthesis of cholesterol (as measured by in vitro conversion of labeled acetate and labeled mevalonate into cholesterol) than .DELTA.4-androstene-17.alpha.-ol-3-one-17.beta.-oic acid and .DELTA.1-testololactone.
Hulcher reported that an analog of mevalonic acid (3,5-dihydroxy-3,4,4-trimethylvaleric acid) strongly inhibits cholesterol biosynthesis by rat liver homogenates.
U.S. Pat. No. 3,983,140 to Endo et al. discloses the fermentation product ML-236B, referred to generically as compactin and mevastatin, which has the structure ##STR3## This compound is prepared by cultivation of a microorganism of the genus Penicillium. The fermentation process is disclosed in U.S. Pat. No. 4,049,495 issued Sept. 20, 1977 to Endo et al.
Brown, A. G., et al., (Beecham Pharmaceuticals Research Div.), "Crystal and Molecular Structure of Compactin, a New Antifungal Metabolite from Penicillium Brevicompactum", J. Chem. Soc. Perkin I. 1165-1170 (1976) confirms that compactin has the complex mevalonolactone structure disclosed by Endo et al. in the above patents.
U.S. Pat. No. 4,231,938 to Monaghan et al. discloses mevinolin (also called lovastatin, Monacolin K, and MK-803), which has the structure ##STR4## This compound is prepared by culturing a microorganism of the genus Aspergillus.
U.S. Pat. No. 4,346,227 to Terahara et al. discloses pravastatin, which has the structure ##STR5##
Pravastatin is prepared by the enzymatic hydroxylation of compactin or its carboxylic acid, as disclosed in U.S. Pat. No. 4,410,629 to Terahara et al.
U.S. Pat. No. 4,448,979, issued May 15, 1984 to Terahara et al., discloses the lactone of pravastatin.
U.S. Pat. Nos. 4,444,784 and 4,450,171 to Hoffman et al disclose various antihypercholesterolemic compounds, including synvinolin (simvastatin), which has the structure ##STR6## The Hoffman patents further disclose compounds of the structures ##STR7## wherein R.sup.1 is H or CH.sub.3, R can be an alkyl group including ##STR8## X, Y and Z are single and/or double bonds in all possible combinations.
European Patent Application No. 0065835A1, filed by Sankyo, discloses cholesterol biosynthesis-inhibiting compounds of the structure ##STR9## The same application discloses the corresponding free carboxylic acids, which may be represented by the formula ##STR10## in which one of R.sup.1 and R.sup.2 represents a hydrogen atom and the other represents a hydroxy group. The Sankyo application further discloses salts and esters of the carboxylic acids.
European patent application No. 251,625A2 describes a series of polyhydro-mevinolin derivatives in which a methyl group has been oxidized and further derivativized to yield compounds following the formulas ##STR11## wherein R is CH.sub.2 OH, CH.sub.2 OC(O)R.sup.3, CO.sub.2 R.sup.4 or C(O)NR.sup.6 R.sup.7 ;
R.sup.1 and R.sup.3 are independently selected from: PA0 R.sup.2 and R.sup.4 are independently selected from: PA0 R.sup.6 and R.sup.7 are independently selected from PA0 X and Y independently are hydrogen, halogen, trifluoromethyl C.sub.1-3 alkyl, nitro, cyano or group selected from: PA0 X and Y are independently hydrogen, halogen, trifluoromethyl, alkyl, nitro, alkoxy, or cyano; PA0 n is 0, 1, or 2; PA0 R.sup.4 is ##STR16## M+ is hydrogen, ammonium, or an alkali metal, such as lithium, sodium, potassium.
(1) C.sub.1-10 alkyl; PA1 (2) substituted C.sub.1-10 alkyl in which one or more substituent(s) is selected from PA1 (3) C.sub.1-10 alkoxy; PA1 (4) C.sub.2-10 alkenyl; PA1 (5) C.sub.3-8 cycloalkyl; PA1 (6) substituted C.sub.3-8 cycloalkyl in which on substituent is selected from PA1 (7) phenyl; PA1 (8) substituted phenyl in which the substituents are X and Y; PA1 (9) amino; PA1 (10) C.sub.1-5 alkylamino; PA1 (11) di(C.sub.1-5 alkyl)amino; PA1 (12) phenylamino; PA1 (13) substituted phenylamino in which the substituents are X and Y; PA1 (14) phenyl C.sub.1-10 alkylamino; PA1 (15) substituted phenyl C.sub.1-10 alkylamino in which the substituents are X and Y; PA1 (16) a member selected from PA1 (17) R.sup.5 S in which R.sup.5 is selected from PA1 (1) hydrogen; PA1 (2) C.sub.1-5 alkyl; PA1 (3) Substituted C.sub.1-5 alkyl in which the substituent is selected from PA1 (4) 2,3-dihydroxypropyl; PA1 (1) hydrogen; PA1 (3) substituted C.sub.1-10 alkyl in which one or more substituent(s) is selected from PA1 (4) C.sub.2-10 alkenyl; PA1 (5) C.sub.3-8 cycloalkyl; PA1 (6) aminocarbonyl; PA1 (7) substituted aminocarbonyl in which one or more substituent(s) is selected from PA1 (8) phenyl; PA1 (9) substituted phenyl in which the substituents are X and Y; PA1 (10) C.sub.1-10 alkylcarbonyl; PA1 (12) phenylcarbonyl; PA1 (13) substituted phenylcarbonyl in which the substituents are X and Y; and PA1 (14) a nitrogen-containing heterocyclic group such as piperidinyl, pyrrolidinyl, piperazinyl, morpholinyl or the like formed by joining the substituents R.sup.6 and R.sup.7 to form a heterocyclic ring; and PA1 (1) alkyl, PA1 (2) substituted alkyl in which one or more substituents are selected from PA1 (3) alkoxy, PA1 (4) alkenyl, PA1 (5) cycloalkyl, PA1 (6) substituted cycloalkyl in which one or more substituents are selected from PA1 (7) phenyl, PA1 (8) substituted phenyl in which one or more substituents are X or Y, PA1 (9) amino, PA1 (10) alkylamino, PA1 (11) dialkylamino, PA1 (12) phenylamino, PA1 (13) substituted phenylamino in which one or more substituents are X or Y, PA1 (14) alkyl(substituted phenyl)amino in which one or more substituents are X or Y, PA1 (15) phenylalkylamino, PA1 (16) di(phenylalkyl)amino, PA1 (17) substituted phenylalkylamino in which one or more substituents are X or Y, PA1 (18) a member selected from PA1 (19) hydroxy substituted alkylamine;
(a) halogen, PA2 (b) hydroxy, PA2 (c) C.sub.1-10 alkoxy, PA2 (d) C.sub.1-5 alkoxycarbonyl, PA2 (e) C.sub.1-5 acyloxy, PA2 (f) C.sub.3-8 cycloalkyl, PA2 (g) phenyl, PA2 (h) substituted phenyl in which the substituents are X and Y, PA2 (i) C.sub.1-10 alkyl S(O).sub.n in which n is 0 to 2, PA2 (j) C.sub.3-8 cycloalkyl S(O).sub.n, PA2 (k) phenyl S(O).sub.n, PA2 (l) substituted phenyl S(O).sub.n in which the substituents are X and Y, and PA2 (m) oxo; PA2 (a) C.sub.1-10 alkyl, PA2 (b) substituted C.sub.1-10 alkyl in which the substituent is selected from PA2 (c) C.sub.1-10 alkyl S(O).sub.n, PA2 (d) C.sub.3-8 cycloalkyl S(O).sub.n, PA2 (e) phenyl S(O).sub.n, PA2 (f) substituted phenyl S(O).sub.n in which the substituents are X and Y, PA2 (g) halogen, PA2 (h) hydroxy, PA2 (i) C.sub.1-10 alkoxy, PA2 (j) C.sub.1-5 alkoxycarbonyl, PA2 (k) C.sub.1-5 acyloxy, PA2 (l) phenyl, and PA2 (m) substituted phenyl in which the substituents are X and Y; PA2 (a) piperidinyl, PA2 (b) pyrrolidinyl, PA2 (c) piperazinyl, PA2 (d) morpholinyl, and PA2 (e) thiomorpholinyl; and PA2 (a) C.sub.1-10 alkyl, PA2 (b) phenyl, and PA2 (c) substituted phenyl in which the substituents are X and Y; PA2 (a) phenyl, PA2 (b) dimethylamino, and PA2 (c) acetylamino; and PA2 (a) halogen, PA2 (b) hydroxy PA2 (c) C.sub.1-10 alkoxy, PA2 (d) C.sub.1-10 alkoxycarbonyl, PA2 (e) C.sub.1-5 acyloxy, PA2 (f) C.sub.3-8 cycloalkyl, PA2 (g) phenyl, PA2 (h) substituted phenyl in which the substituents are X and Y, PA2 (i) C.sub.1-10 alkyl S(O).sub.n in which n is 0 to 2. PA2 (j) C.sub.3-8 cycloalkyl S(O).sub.n, PA2 (k) phenyl S(O).sub.n, PA2 (l) substituted phenyl S(O).sub.n in which the substituents are X and Y, and PA2 (m) oxo; PA2 (a) C.sub.1-5 alkyl, PA2 (b) C.sub.3-8 cycloalkyl, PA2 (c) phenyl, and PA2 (d) substituted phenyl in which the substituents are X and Y; PA2 (a) halogen, PA2 (b) hydroxyl, PA2 (c) alkoxy, PA2 (d) alkoxycarbonyl, PA2 (e) acyloxy, PA2 (f) cycloalkyl, PA2 (g) phenyl, PA2 (h) substituted phenyl in which one or more substituents are X or Y, PA2 (i) alkyl-S(O).sub.n, PA2 (j) cycloalkyl-S(O).sub.n, PA2 (k) phenyl-S(O).sub.n, PA2 (l) substituted phenyl-S(O).sub.n in which one or more substituents are X or Y, and PA2 (m) oxo, PA2 (a) alkyl, PA2 (b) substituted alkyl in which one or more substituents are selected from PA2 (c) alkyl-S(O).sub.n, PA2 (d) cycloalkyl-S(O).sub.n, PA2 (e) phenyl-S(O).sub.n, PA2 (f) substituted phenyl-S(O).sub.n in which one or more substituents are X or Y, PA2 (g) halogen, PA2 (h) hydroxy, PA2 (i) alkoxy, PA2 (j) alkoxycarbonyl, PA2 (k) acyloxy, PA2 (l) phenyl, and PA2 (m) substituted phenyl in which one or more substituents are X or Y, PA2 (a) piperidinyl, PA2 (b) pyrrolidinyl, PA2 (c) piperazinyl, PA2 (d) morpholinyl, PA2 (e) thiomorpholino, PA2 (f) histaminyl, PA2 (g) 3-aminomethyl pyridinyl, and
(i) halogen, PA3 (ii) hydroxy, PA3 (iii) C.sub.1-10 alkoxy, PA3 (iv) C.sub.1-5 alkoxycarbonyl, PA3 (v) C.sub.1-5 acyloxy, PA3 (vi) phenyl, PA3 (vii) substituted-phenyl in which the substituents are X and Y, PA3 (viii) C.sub.1-10 alkyl S(O).sub.n, PA3 (ix) C.sub.3-8 cycloalkyl S(O).sub.n, PA3 (x) phenyl S(O).sub.n, PA3 (xi) substituted phenyl S(O).sub.n in which the substituents are X and Y and PA3 (xii) oxo, PA3 (i) halogen, PA3 (ii) hydroxy, PA3 (iii) alkoxy, PA3 (iv) alkoxycarbonyl PA3 (v) acyloxy PA3 (vi) phenyl PA3 (vii) substituted phenyl in which one or more substituents are X or Y, PA3 (viii) alkyl-S(O).sub.n, PA3 (ix) cycloalkyl-S(O).sub.n, PA3 (x) phenyl-S(O).sub.n, PA3 (xi) substituted phenyl-S(O) in which one or more substituents are X or Y, and PA3 (xii) oxo,
(1) R.sup.8 O(CH.sub.2).sub.m in which m is 0 to 3 and R.sup.8 is hydrogen, C.sub.1-3 alkyl or hydroxy-C.sub.2 -3 alkyl;
(2) ##STR12## in which R.sup.9 is hydrogen, C.sub.1-3 alkyl, hydroxy-C.sub.2-3 alkyl, phenyl, naphthyl, amino-C.sub.1-3 alkyl, C.sub.1-3 alkylamino-C.sub.1-3 alkyl, di(C.sub.1-3 alkyl)amino-C.sub.1-3 alkyl, hydroxy-C.sub.2-3 alkylamino-C.sub.1-3 alkyl or di(hydroxy-C.sub.2-3 alkyl)amino-C.sub.1-3 alkyl;
(3) ##STR13## in which R.sup.10 is hydrogen, C.sub.1-3 alkyl, hydroxy-C.sub.2-3 alkyl, C.sub.1-3 alkoxy-C.sub.1-3 alkyl, phenyl or naphthyl;
(4) R.sup.11 R.sup.12 N(CH.sub.2).sub.m, ##STR14## in which R.sup.11 and R.sup.12 independently are hydogen, C.sub.13 alkyl, hydroxy-C.sub.2-3 alkyl or together with the nitrogen atom to which they are attached form a heterocyclic group selected from piperidinyl, pyrrolidinyl, piperazinyl, morpholinyl or thiomorpholinyl;
(5) R.sup.13 S(O.sub.n (CH.sub.2).sub.m in which R.sup.13 is hydrogen, C.sub.1-3 alkyl, amino, C.sub.1-3 alkylamino or di(C.sub.1-3 alkyl)amino;
and wherein a, b and c each represent single bonds or one of a, b and c represents a double bond or both a and c represent double bonds; or a pharmaceutically acceptable salt thereof.